Question 4

College Answer

In this setting thrombocytopenia may be due to decreased platelet production, increased consumption or aggregation. This question should have been approached as a simple practical problem. One needs to obtain a complete history to understand whether this is an acute or a chronic problem, whether the patient is on platelet lowering drugs, did it coincide with heparin use, is there evidence of sepsis, DIC, is there a history of SLE, ITP, malaria etc. Investigations will include heparin antibody, blood film coagulation screen, and DIC screen. If no other cause is found, marrow aspiration may be indicated. Management will consist of ceasing heparin and other implicated drugs, treating underlying infection, platelet transfusion if bleeding occurs or if surgery is contemplated.

Discussion

The college insists we approach this as "a simple practical problem". However, one should not that they do not ask one to make a diagnosis, but how would you manage the problem without knowing the cause?

Well.

The following list of generic steps applies to thrombocytopenia of any cause:

Minimise platelet destruction

• Withhold heparin and rationalise the indications for heparin, eg.:
  • Use alternative anticoagulants for the extracorporeal circuit (citrate comes to mind but there are numerous others) 
  • Use mechanical thromboprophylaxis or LMWH
  • Rationalise the use of dialysis
• Manage the sepsis with appropriate antibiotics and resuscitation (as sepsis improves, DIC will resolve)
• Address specific destructive aetiologies with appropriately targeted therapies, eg.:
  • Plasmapheresis for TTP
  • High dose methylprednisone for MAHA
  • Delivery for HELLP

Maximise platelet production

• Ensure supply of haematinics is uninterrupted
• Optimise nutrition, focusing on vitamins and trace elements
• Withhold or rationalise any drugs which are bone marrow toxins
• Correct the correctable causes of bone marrow failure and liver disease
• Think about thrombopoietin receptor agonists (eg. eltrombopag) - some promising results have come from the RAISE trial (Cheng et al, 2010)

Protect the patient from complications of thrombocytopenia

• Cancel or postpone all nonessential invasive procedures
• Cover unavoidable procedures with transfusion of pooled platelets (up to a level of 50)
• For neurosurgical procedures (or lumbar puncture, etc) aim for a level above 100
• Otherwise, keep the level above 20
  (the above numbers derived from recommendations made by Van der Linden et al, 2012)

Diagnosis is more complicated. The differential diagnosis of thrombocytopenia is broad:

Causes of Thrombocytopenia

Decreased platelet production Bone marrow suppression Alcohol toxicity Chemotherapy Congential causes, eg. Fanconi anaemia Myelofibrosis or aplastic anaemia Neoplasm, eg. leukaemia or lymphoma Viral infection, eg. HIV, EBV, Hep C, parvovirus, mumps, rubella, varicella... Nutritional deficiency: B12 and folate deficiency Liver disease - decreased production of thrombopoietin (TPO)	Increased platelet destruction SLE ITP DIC Drugs: Quinine Heparin Valproate Post-transfusion thrombocytopenia Microangiopathic haemolytic anaemia Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) Antiphospholipid syndrome HELLP syndrome in pregnancy Physical destruction in the cardiopulmonary bypass apparatus or circuit
Pseudothrombocytopenia The sample was improperly anticoagulated, and there is platelet clumping on microscopy of the blood film. Send a citrated tube instead- often the EDTA is to blame. Abciximab can cause this, as it is an antibody to the GP IIb/IIIa receptor.	Dilution of platelets Massive transfusion Massive fluid resuscitation Sequestration Hypersplenism Accessory spleens or splenunculi Hepatic sequestration Extremes of hypothermia

In order to simplify one's answer, one may be able to narrow this range to the causes which are relevant to the critically septic patient on dialysis:

• Artifact
  • Diluted sample
  • Platelet aggregates
• Decreased production
  • Antibiotic-associated thrombocytopenia (eg. linezolid)
  • Sepsis-associated bone marrow suppression
  • Preexisting condition (eg. malignancy)
• Increased destruction
  • Consumption in DIC
  • Consumption by dialysis circuit
  • Consumption due to HITS
  • Autoimmune destruction
• Sequestration
  • Hypersplenism

This is a more manageable list.

One would organise the following investigations in order to work through it:

• Peripheral blood smear, and a repeat platelet count in a citrated tube
• DIC screen: coagulation tests, D-dimers and fibrinogen
• Vitamin B12 level and full blood count
• HITTS screen: anti-platelet factor 4 antibody and platelet aggregation tests
• Autoimmune screen, including tests for SLE and other vasculitic diseases
• ADAMTS13 screening for TTP
• Bone marrow biopsy

The links point to brief explanatory notes for these tests, which one may find in the local chapter on thrombocytopenia.